Palladium Hiyama coupling

Pitavastatin (3) was launched in 2003 and is currently marketed in Japan under the trade name Livalo . Like rosuvastatin and fluvastatin, pitavastatin is a completely synthetic HMG-CoA reductase inhibitor that was developed by Kowa, Nissan Chemical, and Sankyo (Sorbera et al., 1998). Multiple syntheses of pitavastatin have been reported and an exhaustive review of these efforts is beyond the scope of this text (Hiyama et al., 1995a, b Minami and Hiyama, 1992 Miyachi et al., 1993 Takahashi et al., 1993, 1995 Takano et al., 1993). Instead, we will focus our discussion on two related and innovative synthetic approaches that differ strategically from the routes we have previously examined for rosuvastatin and fluvastatin. These routes to pitavastatin employed palladium-mediated coupling reactions to install the 3,5-dihydroxyheptanoic acid side-chain. This key retrosynthetic disconnection is highlighted in Scheme 12.6, in which a suitable functionalized side-chain (52 or 53) is attached to the heterocyclic core of pitavastatin (51) through palladium-mediated coupling. 

The Hiyama Coupling is the palladium-catalyzed C-C bond formation between aryl, alkenyl, or alkyl halides or pseudohalides and organosilanes. This reaction is comparable to the Suzuki Coupling and also requires an activating agent such as fluoride ion or a base. 

Clarke recently published the first microwave-accelerated Hiyama coupling [163,164]. It was noted that the availability and nontoxic attributes of the organosilicon reactants make them very attractive in synthesis, but their low nucleophilicity limits their potential. Microwave heating allowed aryl bromides and activated aryl chlorides to react under palladium catalysis using an electron-rich N-methyl piperazine/cyclohexyl phosphine ligand (Scheme 75). A vinylation reaction with vinyltrimethoxysilane was also reported [164],... 

Denmark and his co-workers recently reported a series of the palladium-catalyzed coupling reactions of alkenylsilicon compounds with aryl iodides. Thus, ( )- or (Z)-alkenylsilacyclobutanes, which are readily prepared by the reaction of the corresponding alkenylaluminum compounds with chlorosila-cylobutanes or the reduction of alkynylsilacyclobutanes, respectively, were found to be active nucleophiles to react with aryl iodides in 10 min at room temperature in most cases (Eq. 13) [17]. Later, it was clarified that silacyclobu-tanes were first converted into alkenyl(propyl)silanols by hydrolysis under the reaction conditions [18], and these were shown to be truly active species. Alkenylsilanols actually react with aryl iodides under the similar conditions (Eq. 14) [19,20]. Independent study by Hiyama and Mori revealed that silver(l) oxide also is an excellent activator for the palladium-catalyzed coupling of alkenylsilanols with an aryl iodide (Eq. 15) [21]. Very recently Denmark... 

Srimani D, Sawoo S, Sarkar A (2007) Convenient synthesis of palladium nanoparticles and catalysis of Hiyama coupling reaction in water. Oig Lett 9 3639-3642... 

Hiyama Coupling. Diphenyldifluorosilane is an effective phenyl transfer reagent for the palladium-catalyzed coupling with aryl iodides (eq 4). It can also be used to prepare biphenyl in high yield when ethyl dibromosenecioate is used as an oxidant (eq 5). ... 

To date, nearly all studies of the Hiyama reaction have focused on couplings of Csp -X electrophiles. Fu developed the first method for achieving the room-temperature Hiyama couplings of unactivated alkyl bromides and iodides. Palladium-catalyzed reactions of alkyl bromides and iodides 18 with aryltrimethoxysilanes 19 in the presence of phosphorus ligand and TBAF afforded coupled products 20 in moderate to good yields. 

From all the palladium cross coupling conditions tried (Suzuki-Miyaura, Heck, Negishi, Hiyama, Kumada-Tamao, Kobayashi, DeShong), only the Stille coupling proved to be reliable on scale over 50 g. It is also interesting to note that adequate work-up allowed for getting below the acceptable upper limit of 20 ppm of stannane content (analytically determined by ICP). 

The C-C bond forming reaction of an organic halide with an organosilane, catalysed by nickel or palladium, is known as the Hiyama cross-coupling. Typically the C-Si bond needs to be activated by either electronegative substituents or by external fluoride anions. 

Bromoalkynes also couple with vinylstannanes readily to result in enynes. Synthesis of protected enynals via cross-coupling of vinylstannanes with 1-bromoalkynes in the presence of a catalytic amount of Pd(II) has been reported (equation 143)252. Hiyama and coworkers extended the Stille methodology for sequential three-component coupling of trimethylstannyl(trimethylsilyl)acetylene with a vinyl iodide in the first step and cross-coupling of the intermediate trimethylsilylethyne with another alkenyl iodide in the presence of tris(diethylamino)sulphonium trimethyldifluorosilicate in the second step to generate a dienyne (equation 144)253. Both steps occur under palladium catalysis, in one-pot, to result in stereodefined l,5-dien-3-ynes. 

In 1996, Hiyama and co-workers reported on the cross-coupling of activated aryl chlorides with aryl- and alkenyl-chlorosilanes 71 (Figure 16). The high temperatures required to activate the aryl chlorides did not affect the organosilanes an added advantage that can be attributed to their relative inertness. The system could be catalyzed by a variety of phosphine-bearing palladium complexes in the presence of either KF or TBAF as promoters. 

Cross-coupling reactions 5-alkenylboron boron compounds, 9, 208 with alkenylpalladium(II) complexes, 8, 280 5-alkylboron boron, 9, 206 in alkyne C-H activations, 10, 157 5-alkynylboron compounds, 9, 212 5-allylboron compounds, 9, 212 allystannanes, 3, 840 for aryl and alkenyl ethers via copper catalysts, 10, 650 via palladium catalysts, 10, 654 5-arylboron boron compounds, 9, 208 with bis(alkoxide)titanium alkyne complexes, 4, 276 carbonyls and imines, 11, 66 in catalytic C-F activation, 1, 737, 1, 748 for C-C bond formation Cadiot-Chodkiewicz reaction, 11, 19 Hiyama reaction, 11, 23 Kumada-Tamao-Corriu reaction, 11, 20 via Migita-Kosugi-Stille reaction, 11, 12 Negishi coupling, 11, 27 overview, 11, 1-37 via Suzuki-Miyaura reaction, 11, 2 terminal alkyne reactions, 11, 15 for C-H activation, 10, 116-117 for C-N bonds via amination, 10, 706 diborons, 9, 167... 

Tsuji-Trost allylation reactions offer multiple pathways to tetrahydrofuran synthesis including C-C bond-formation steps. A palladium-catalyzed sequence of allylic alkylation and Hiyama cross-coupling provides a convenient synthesis of 4-(styryl)-lactones (Scheme 67) <2006SL2231>. 

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